1. Field of Invention
The present invention relates, in general, to chemical compounds having antiproliferative and antimitotic activity. More specifically, the present invention is directed to novel 2-alkoxy estradiols having antiproliferative and antimitotic activity and to methods of preparing and using these novel compounds.
2. Description of the Related Art
Certain 2-alkoxy estradiols have been discovered to have antitumor activity (U.S. Pat. No. 6,136,992; U.S. Pat. No. 6,054,598; U.S. Pat. No. 6,051,726; U.S. Pat. No. 5,892,069; U.S. Pat. No. 5,661,143; U.S. Pat. No. 5,504,074; WO 95/04535) (all patents cited throughout this specification are incorporated herein by reference). 2-Methoxyestradiol (2-ME2) is one such 2-alkoxy estradiol exhibiting antitumor activity (U.S. Pat. No. 5,892,069; U.S. Pat. No. 5,661,143; U.S. Pat. No. 5,504,074; WO 95/04535) 2-Methoxyestradiol is an endogenous mammalian metabolite formed by the sequential biochemical hydroxylation and methylation of the natural hormone estradiol (Breuer, H. et al., Naturwissenschaften 12, pp. 280-281 (1960)).
Recent studies have demonstrated that the mechanism responsible for the antitumor activity exhibited by certain 2-alkoxy estradiols, including 2-ME2, Includes interference with or prevention of cell mitosis, the multi-step process that preceeds cell division and replication (Alberts, B. et al., The Cell, pp. 652-661 (1989); Stryer, L., Biochemistry (1988)). For example, some 2-alkoxy estradiols have been shown to inhibit the replication of certain cancer cells by interfering with microtubule formation and function (Seegers, J. C. et al., J. Steroid Biochem. 32, pp. 797-809 (1989); U.S. Pat. No. 6,136,992; U.S. Pat. No. 6,054,598; U.S. Pat. No. 6,051,726; U.S. Pat. No. 5,892,069; U.S. Pat. No. 5,661,143; U.S. Pat. No. 5,504,074; WO 95/04535). Microtubules facilitate and make possible, among other things, chromosome and organelle movement and segregation during cell mitosis (Stryer, L., Biochemistry (1988)). Preventing or interfering with microtubule formation and function leads to mitotic arrest and frequently to apoptosis. In addition to cancer, many diseases are characterized by undesirable cell proliferation, and the value of compounds and methods that prevent such undesirable cell proliferation is of great importance to the treatment of such diseases. Microtubule formation and function is also critical to cell maintenance, locomotion and the movement of specialized cell structures such as cilia and flagella (Stryer, L., Biochemistry (1988)).
To function properly, cilia and flagella require proper tubulin polymerization (U.S. Pat. No. 6,162,930). Certain 2-alkoxy estradiols are known to inhibit tubulin polymerization or to cause the formation of tubulin polymer with altered morphology and stability properties (U.S. Pat. No. 6,136,992). By interfering with normal microtubule dynamics, such compositions may be used to treat those diseases characterized by abnormal proliferation.
Certain 2-alkoxy estradiols, including 2-ME2, have also been demonstrated to act as antiangiogenic agents (Fotsis et al., Nature 368, pp. 237-239 (1994); U.S. Pat. No. 6,136,992; U.S. Pat. No. 6,054,598; U.S. Pat. No. 6,051,726; U.S. Pat. No. 5,892,069; U.S. Pat. No. 5,661,143; U.S. Pat. No. 5,504,074; WO 95/04535). Such antiangiogenic activity is likely due to the arrest of endothelial cell mitosis and the consequent prevention of endothelial cell proliferation. 2-alkoxy estradiols exhibiting antiangiogenic activity may be used to treat diseases in which angiogenesis plays an important role. Inducing mitotic arrest and preventing angiogenesis will cause tumors to shrink, and the combination of these methods will provide significant advantages over current anticancer therapies. 2-alkoxy estradiols in murine models have been shown to be orally active, and to exhibit no appreciable toxicity at therapeutically effective doses (Fotsis et al., Nature 368, pp. 237-239 (1994)).
In general, there is a need in the art to identify additional antiproliferative and antimitotic chemical compounds which provide therapeutic advantages over those compounds currently known and used. Additionally, there is a need to improve the method of synthesis of such compounds in order to provide greater efficiency, yield, and purity in their production.